阅读说明：本技术 一种以青霉素钾盐为原料制备头孢维星的中间体异构化物及其制备方法 (Intermediate isomeride for preparing cefuroxime from penicillin sylvite and preparation method thereof ) 是由 郭胜超 王光明 何东贤 邵倩 李艳 刘艳 余佳 于 2020-07-31 设计创作，主要内容包括：本发明公开了一种以青霉素钾盐为原料制备头孢维星的中间体异构化物及其制备方法,以中间体开环重排物为原料,异构化反应得到中间体异构化物,具体在反应容器中加入脱水后的反应有机溶剂,然后加入中间体氧化物,调节温度90-100℃,搅拌至溶液澄清,加入亚磷酸三甲酯,调节真空度,控制反应温度为90-100℃,反应至反应完全,氮气保护下冷至30℃以下,在反应容器中加入有机碱,氮气保护下30℃以下避光反应至反应完全得到中间体异构化物。与现有步骤相比,在合成到本发明的中间体时,采用一锅法的方法制备,降低操作的难度。由于头孢母核稳定性较差,本发明通过反应条件的严格控制,使得反应的选择性提高,最终使得反应收率高,产品质量好。(The invention discloses an intermediate isomeride for preparing cefuroxime from a penicillin potassium salt as a raw material and a preparation method thereof, wherein an intermediate ring-opening rearrangement product is used as a raw material to carry out isomerization reaction to obtain the intermediate isomeride, a dehydrated reaction organic solvent is added into a reaction vessel, an intermediate oxide is added, the temperature is adjusted to 90-100 ℃, the mixture is stirred until the solution is clarified, trimethyl phosphite is added, the vacuum degree is adjusted, the reaction temperature is controlled to 90-100 ℃, the reaction is carried out until the reaction is completed, the reaction temperature is cooled to below 30 ℃ under the protection of nitrogen, organic base is added into the reaction vessel, and the reaction is carried out in a dark place at the temperature below 30 ℃ under the protection of nitrogen until the reaction is completed to obtain. Compared with the prior steps, the intermediate is prepared by adopting a one-pot method when being synthesized, so that the operation difficulty is reduced. Because the stability of the cephalosporin nucleus is poor, the invention improves the selectivity of the reaction by strictly controlling the reaction conditions, and finally ensures that the reaction yield is high and the product quality is good.)

1. A preparation method for preparing an intermediate isomeride of cefuroxime by taking penicillin sylvite as a raw material is characterized in that an intermediate ring-opening rearrangement is taken as a raw material, and an intermediate isomeride is obtained through isomerization reaction, wherein the reaction formula is as follows:

2. the process for preparing an intermediate isomer of cefoweixin using penicillin potassium salt as a raw material as claimed in claim 1, wherein the synthesis of the intermediate ring-opening rearrangement product is: the intermediate oxide is subjected to ring-opening rearrangement to obtain an intermediate ring-opening rearrangement product, and the reaction formula is as follows:

3. the process for the preparation of intermediates isomerate of cefoweixin starting from potassium penicillin as claimed in claim 2, characterized by the synthesis of the intermediate oxides: taking penicillin sylvite as a raw material, carrying out esterification reaction with p-nitrobenzyl bromide, and reacting the esterification reaction product with peroxyacetic acid to obtain an intermediate oxide, wherein the reaction formula is as follows:

4. the process for preparing an intermediate isomer of cefotaxime from penicillin potassium salt as claimed in claim 2, wherein the intermediate ring-opening rearrangement and the intermediate isomer are prepared by one-pot method.

5. The method for preparing the intermediate isomeride of the cefuroxime starting from the potassium salt of penicillin as claimed in claim 4, wherein the specific operation steps for preparing the intermediate ring-opening rearrangement product and the intermediate isomeride by the one-pot method are as follows: adding a dehydrated reaction organic solvent into a reaction vessel, then adding an intermediate oxide, adjusting the temperature to 90-100 ℃, stirring until the solution is clear, adding trimethyl phosphite, controlling the reaction temperature to 90-100 ℃, reacting until the reaction is complete, and cooling to below 30 ℃ under the protection of nitrogen;

and adding organic base into the reaction vessel, and reacting under the protection of nitrogen and at the temperature of below 30 ℃ in a dark place until the intermediate isomeride is completely obtained.

6. The process for the preparation of intermediates isomerate of cefoweixin starting from the potassium salt of penicillin as claimed in claim 5, characterized in that: the organic base is ammonia organic base.

7. The process for the preparation of intermediates isomerate of cefoweixin starting from the potassium salt of penicillin as claimed in claim 6, characterized in that: the organic base is one of triethylamine, diethylamine, pyridine, tetramethylguanidine and N, N-diisopropylethylamine.

8. The process for the preparation of an intermediate isomer of cefuroxime as claimed in any of claims 3 to 5, starting from the potassium salt of penicillin, characterized in that: after the reaction is finished, adding dilute hydrochloric acid for neutralization, stirring, standing for layering, adding an extraction organic solvent into a water layer for extraction, washing an organic layer with brine, concentrating until the organic layer is dried to obtain a crude product, and recrystallizing with methanol to obtain the product.

9. The process for the preparation of intermediates isomerate of cefotaxime from the potassium salt of penicillin as claimed in claim 8, wherein: the reaction organic solvent is toluene or a mixed solvent which can form an azeotropic system with the toluene and has a boiling point of 90-100 ℃; the extraction organic solvent is chloroform or dichloromethane.

10. An intermediate isomeride for preparing cefuroxime from penicillin sylvite is characterized in that the structural formula is as follows:

Technical Field

The invention relates to a medical intermediate, in particular to an intermediate isomeride for preparing cefuroxime by taking penicillin sylvite as a raw material and a preparation method thereof.

Background

The cefuroxime is a third generation cephalosporin medicament, and the molecular structure of the cefuroxime is as follows:

cefotaxime was first successfully synthesized by Smithkline Beecham company in 1994, but the synthesis cost was higher, and then developed as a pet exclusive drug by fevered, was first allowed in the european union for the treatment of skin infections of cats and dogs in 2006, and was not allowed in the us until 2008 for the treatment of skin and soft tissue infections of cats and dogs, compared to the three cephalosporin (cephradine, cefpodoxime proxetil, ceftiofur) drugs that have been used, cefotaxime has a better antibacterial activity, a higher bioavailability and a longer elimination half-life.

The preparation of cefoweixin, a preparation method published by Pfizer company, is to take penicillin G as a raw material, firstly protect 2-hydroxy with benzyl chloroformate, then sequentially carry out ozonization and epoxidation on 4-hydroxy, remove CBZ protecting group by catalytic hydrogenation, and then prepare cefoweixin through 8 steps of reactions such as ring-opening amination and amidation. The method has the problems of long route, low yield, harsh reaction conditions, high environmental protection requirement and large operation difficulty. Therefore, the applicant designs a novel preparation method of cefuroxime.

Disclosure of Invention

In view of the above technical problems, a first object of the present invention is to provide a method for preparing an intermediate isomer of cefotaxime from a potassium salt of penicillin, and a second object of the present invention is to provide an intermediate isomer for preparing cefotaxime.

In order to achieve the first object, the invention provides a preparation method for preparing an intermediate isomer of cefuroxime from a potassium penicillin salt, which is characterized by comprising the following steps: taking the intermediate ring-opening rearrangement product as a raw material, and carrying out isomerization reaction to obtain an intermediate isomeride, wherein the reaction formula is as follows:

the intermediate isomeride reacts with ozone to obtain an intermediate acetic ester compound, and the reaction formula is as follows:

reducing the intermediate acetate compound to obtain an intermediate hydroxylate, wherein the reaction formula is as follows:

and finally obtaining the cefoweixin through the subsequent design steps of the intermediate hydroxylate.

The synthesis of the intermediate ring-opening rearrangement product comprises the following steps: the intermediate oxide is subjected to ring-opening rearrangement to obtain an intermediate ring-opening rearrangement product, and the reaction formula is as follows:

synthesis of intermediate oxide: taking penicillin sylvite as a raw material, carrying out esterification reaction with p-nitrobenzyl bromide, and reacting the esterification reaction product with peroxyacetic acid to obtain an intermediate oxide, wherein the reaction formula is as follows:

during the preparation, the intermediate ring-opening rearrangement product and the intermediate isomeride are prepared by a one-pot method.

The specific operation steps for preparing the intermediate ring-opening rearrangement product and the intermediate isomeride by the one-pot method are as follows: adding a dehydrated reaction organic solvent into a reaction vessel, then adding an intermediate oxide, adjusting the temperature to 90-100 ℃, stirring until the solution is clear, adding trimethyl phosphite, controlling the reaction temperature to 90-100 ℃, reacting until the reaction is complete, and cooling to below 30 ℃ under the protection of nitrogen;

and adding organic base into the reaction vessel, and reacting under the protection of nitrogen and at the temperature of below 30 ℃ in a dark place until the intermediate isomeride is completely obtained.

The molar ratio of the intermediate oxide to trimethyl phosphite (TMP) is 1:1.1-2.0, and the molar ratio of the intermediate oxide to the organic base is 1: 1.3-3.0.

The one-pot method is adopted to prepare the intermediate ring-opening rearrangement product and the intermediate isomeride, the operation is simple, the yield of the two-step reaction can reach 80 percent, and the yield is high. The isomerization adopts organic base which is weaker than inorganic base in alkalinity, and the reaction conditions (reaction temperature, feeding mode, feeding steps, molar ratio and the like) are strictly controlled to avoid the reaction of functional groups at other positions of the cephalosporin nucleus. Meanwhile, nitrogen protection and light-shielding reaction are adopted, so that the selectivity of the reaction is improved, the reaction yield is improved, and the quality of a reaction product is improved.

In the above scheme, the organic base is an ammonia organic base.

Preferably: the organic base is one of triethylamine, diethylamine, pyridine, tetramethylguanidine and N, N-diisopropylethylamine. Moderate alkalinity and improved reaction selectivity.

In the scheme, the method comprises the following steps: after the reaction is finished, adding dilute hydrochloric acid for neutralization, stirring, standing for layering, adding an extraction organic solvent into a water layer for extraction, washing an organic layer with brine, concentrating until the organic layer is dried to obtain a crude product, and recrystallizing with methanol to obtain the product. The product quality is improved by methanol recrystallization.

In the scheme, the method comprises the following steps: the reaction organic solvent is toluene or a mixed solvent which can form an azeotropic system with the toluene and has a boiling point of 90-100 ℃; the extraction organic solvent is chloroform or dichloromethane. Toluene is used as an organic solvent, so that the temperature of the reaction can be met. Other solvents are added into toluene to form an azeotropic system, so that the boiling point is just between 90 and 100 ℃, and the reflux reaction is carried out during the reaction, thereby ensuring that the reaction is easier to control.

The toluene dehydration step is as follows: adding toluene into the container, heating to about 80 ℃, adjusting the vacuum degree and reflux amount, and performing reduced pressure reflux dehydration.

In the above scheme, the synthesis of the intermediate oxide: adding DMF and p-nitrobenzyl bromide into a reaction vessel, dissolving at room temperature for clarification, adding penicillin potassium salt, heating to 42-45 ℃, stirring for reaction, adding a mixed solution of dichloromethane and water after the reaction is finished, adjusting the pH value of a sulfuric acid solution to be less than 5, standing for layering, and removing a water layer;

dropwise adding peroxyacetic acid into the organic layer, stirring and reacting until the reaction is complete, adding water, standing for layering, removing the water layer, adding a sodium sulfite solution into the organic layer for reacting until the material is non-oxidative, adding a sodium bicarbonate aqueous solution for cleaning, layering, removing the water layer, concentrating the organic layer until the organic layer is dried to obtain a crude product, and recrystallizing methanol to obtain the product.

Preferably, the molar ratio of the penicillin potassium salt to the p-nitrobenzyl bromide is 1.0:1.0-1.2, and the molar ratio of the penicillin potassium salt to the peroxyacetic acid is 1: 1.5-3.

The method directly adds peroxyacetic acid to oxidize the esterification product without treatment to obtain an intermediate oxide, equivalently adopts a one-pot method for preparation, and has the advantages of simple operation and high yield, and the total yield of the two-step reaction can reach 90 percent.

The ozone oxidation and reduction is prepared by a one-pot method, and the method comprises the following specific steps:

ozonization, adding an ozonization reaction solvent and an intermediate isomeride into a container, stirring under the protection of nitrogen, cooling to a temperature lower than-70 ℃, introducing ozone until the reaction is complete, and then introducing nitrogen to drive away ozone gas in the system until no ozone residue exists in the system;

reducing, adding acetic acid and a solvent, controlling the temperature below minus 60 ℃, adding a sodium borohydride solution prepared from the solvent and water, stirring and reacting until the reaction is complete, after the reaction is finished, adding sodium metabisulfite, stirring, standing and layering, keeping an organic layer, adding dichloromethane into a water layer for extraction, combining the organic layers, adjusting the pH value to 5-6, adding water and brine for washing, concentrating under reduced pressure until a solid is separated out, filtering, washing and drying to obtain the product.

The molar ratio of the intermediate isomeride to the sodium borohydride is 1: 1.01-1.5.

The method adopts ozone for oxidation, sodium borohydride for reduction, and improves the selectivity of the reaction by controlling the conditions of reaction temperature, selected solvent and the like, so that other functional groups are not reacted. The ozonization is directly reduced without treatment, a one-pot method is adopted, the yield of the two-step reaction can reach 75 percent, the operation is simple, the yield is high, and the reaction selectivity is good.

The ozonization reaction solvent is a mixed solution of dichloromethane and one of isopropanol, THF and acetone.

The solvent added during reduction is isopropanol or tetrahydrofuran or acetone.

The second object of the present invention is achieved by: an intermediate isomeride for preparing cefuroxime from penicillin sylvite is characterized in that the structural formula is as follows:

the invention has the beneficial effects that the intermediate of the other preparation method of the cefvistin is prepared by taking the potassium penicillin as the raw material, and compared with the prior steps, the intermediate is prepared by adopting a one-pot method for many times when being synthesized, so that the operation difficulty is reduced. Because the stability of the cephalosporin nucleus is poor, the invention improves the selectivity of the reaction by strictly controlling the reaction conditions, and finally ensures that the reaction yield is high and the product quality is good.

Detailed Description

The invention is further illustrated by the following examples: